Quaternary ammonium containing compounds containing fluoroalkyl monocyclic aromatic hydrocarbon groups



Patented Oct. 19, 1954 QUATERNA-RY AMMONIUM CONTAINING COMPOUNDS CONTAINING FLUO-RO- ALKYL MONOCYCLIC AROMATIC HY- DROCARBON GROUPS Bruno H. Wojcik, Niagara Falls, N. Y., assignoi to Hooker Electrochemical Company, Niagara Falls, N. Y., a corporation of New York No Drawing. Application May 2, 1950, Serial N0. 159,668

9 Claims.

This invention relates to a new class of quaternary amines and, more particularly, to quaternary amines containing fluorine and processes for their preparation.

I have advanced the quaternary amine art by providing a novel group of such amines having one or more fluorine atoms attached to a carbon atom of the cationic radical.

The cationic radical may have the fluorine atom or atoms attached to a carbon atom in any portion of its structure, according to my invention. Thus, in quaternary amines having a cationic radical having alkyl groups of varying chain lengths, as two lower alkyl (C1 to C8) groups, and a higher alkyl (C9 to C18) group, along with a ringcontaining group, attached to the pentavalent nitrogen atom, the fluorine may be present as a substituent on any one or more of the carbon atoms of these groups.

Many of the compounds of my invention are crystalline substances, which may be dissolved in water. They are substantially odorless and practically non-toxic to mammals.

A comparison of the bactericidal or germicidal properties of the compounds of this invention with those of a commercial prior art quaternary compound, dodecyldimethylbenzyl ammonium chlo ride, which has a phenol coefficient at 20 degrees centigrade against E. typhz' of about 250, and against S. aureus of about 280, shows that my compounds are considerably more potent as germicides; dodecyldimethyl 3 (trifluoromethyD- benzylammonium chloride, for example, being about three times more eiiective. The other compounds of my invention possess like disinfecting properties.

An acute toxicity determination indicates that certain of the compounds of my invention are substantially less toxic than the corresponding quatternary amines not containing fluorine in the cationic portion of the molecule. For example, the product of Example VII; namely, dodecyldimethyl 3 (trifluoromethyl)benzylammonium chloride, has been found by acute toxicity determinations to be about ten times less toxic than dodecyldimethylbenzylammonium chloride,

Skin irritation tests on humans show that certain of the compounds of my invention are also non-sensitizers, dodecyldimethyl 3 (trifluoromethyl) benzylammonium chloride being less irri- 2 tant than the quaternary amines commercially available for germicidal use.

The anion attached to the pentavalent nitrogen atom of my compounds is preferablyselected from the group of anions of organic and inorganic acids, such as the halides (including fluorine), nitrates, cyanides, hydroxides, sulfates, alkyl sulfates, phosphates, orthophosphate's, or the salts with organic acids, for instance, the iormates, acetates, lactates, 'tartr'ates, citrates, benzene or toluene sulfonates, 'benzoat'es, salicylates, hydrocinnamates, et cetera.

More particularly, this invention includes compounds of the above general type wherein two lower alkyl groups are attached to the pentavalent nitrogen atom or, the said nitrogen atom is part of a heterocyclic radical, i. e., an N-heterocycle; one higher alkyl group of about 9 to 18 carbon atoms, including odd number carbon branched-chain groups resulting from the 0x0 process, is attached to said nitrogen atom, and, an alkyl-aralkyl or alkyl-cycloa-lkylalkyl group containing at least one fluorine atom and preferably as a trifiuoromethyl group, is attached to said nitrogen atom. Still further this invention preferably includes those quaternary amines which contain attached to the nitrogen atom, an aralkyl group having a trifiuoromethyl group in the meta position.

The preferred quaternary amines of this invention having a ring-containing group attached to the pentavalent nitrogen atom with at least one fluorine atom attached to said group can be prepared by reacting stoichiometric amounts of a salt such as the chloride, sulfate, et ceter'a, of the ring-containing group containing fluorine with the selected tertiary amine. The reaction is conducted at room temperature for a period of about six hours and then the reaction mixture is heated for approximately ten hours at a temperature of about 80 to 100 degrees centigrade to complete the reaction. Alternatively, the two reactants may simply be placed in a reaction vessel, mixed, andv heated to the reaction temperature immediately thereafter. The reaction may be effected in anor by removing impurities by vacuum or steam 3 distillation. Other quaternary amines of my invention may be prepared by reacting a substituted tertiary amine containing fluorine in an alkyl group, with an organic salt.

The following examples are illustrative of the invention:

Example I .-Decyldimethyl-4- (trifluoromethyl) benzylammom'um chloride Two and ninety-two hundredths parts (0.015 mole) of 4-(trifluoromethyl)benzyl chloride was reacted with 2.6 parts (0.014 mole) of decyldimethylamine by heating a mixture of the reactants at a temperature of about 80 degrees cen- C2oHa3C1F3N; calcd. 9.33% CI; found 9.28% CI.

In a manner after Example I, the following compounds were prepared, in the yields indicated, in accordance wtih the reactions as illustrated below.

Example II.DodecyZdlmethyl-4- (trifluoromethyl) benzylammomum chloride (CHmNCwHzs It analyzed as follows: CzzHszClFsN; 86% yield;

calcd. 8.71% Cl; found 8.69% Cl.

Example III. Tetradecyldimethyl-el- (trz'jluoromethyl) benzylammo'nium chloride (CHa)zNCnH2n CHzCl It analyzed as follows: C24H41C1F3N; 80% yield;

calcd. 8.14% Cl; found 8.05% Cl.

Example IV.-Hexadecyldimethyl-4- (trifluoromethyl) benzylammonium chloride CH: v CHI CuHas ahNCuHu It analyzed as follows: C2eH45C1F3N; 85% yield; calcd. 7.65% Cl; found 7.70% Cl.

CHnCl 4 Example V.-Octadecyldimethyl-4-(trifluoromethyl) benzylammomum chloride I lai1 'I- 8)2N 1a a1 o F; o F;

It analyzed as follows: C28H49C1F3N; yield; calcd. 7.20% CI; found 7.13% Cl.

' Example VI .DecyZdimethyl-3-(trifluoromethyl) benzylammonium chloride CHrCl It analyzed as follows: C20H35C1F3N 63% yield; calcd. 9.30% Cl; found 9.82% C1.

Example VI I .-Do.decyldimethyZ-3- (trifluoromethyl) benzylammomum chloride HSMNC Hn 0 Fa C Fa It analyzed as follows: Czzl-lswclFaN; 88% yield; calcd. 8.70% Cl; found 8.70% 01..

Example VII I .Tetradecyldimethyl-3- (trifluoromethyl) benzylammom'um chloride (CHahNC Hzn C F; C F:

It analyzed as follows: C24H41C1F3N; 72% yield; calcd. 8.14% Cl; found 8.24% Cl.

Example IX.HexadecyldimethyZ-3- (trifiuoromethyl) beneylammom'um chloride CHaCl CHr-N-Cl I CxeHa:

(CHahNCmHas C Fa C F:

It analyzed as follows: C26H45C1F3N; 87% yield; calcd. 7.65% CI; found 7.62% Cl.

Example X.-Octadecyldimethyl-3-(trifluoromethyl) benzylammom'um chloride It analyzed as follows: C2aH49C1F3N; 88% yield; calcd. 7.20% Cl; found 7.22% 01.

Example XI.Decyldimethyl-3,5-bis(trifluoromethyDbenzylammonium chloride CE! /CH: CHaCl CHr-N-Cl Cm n mNCmHn C F C Fl C F C F;

'Itanaly'zed as follows: CzaI-LisClFeN; 78% yield; calcd. 7.45%(3'1; found 7.40% CI.

Example XI l I .Tetradecyldimethyl-3,5 -bis (trifluoromethyl) benzylammomum chloride CH1 CH OHr-N-Ol CuHzo It analyzed'asfollowsz C25H40C1F6N; 68% yield; calcd. 7.04% C1; found 7.05 C1.

Example XI V.-H ewadecyldimethyZ-3,5 -bis (triflaoromethyl) benzylammonium chloride CH3 CH3 GHz-N-CI mHaa omol

+ (CHa)zNCiaHaa OF C F: C'Fg It analyzed as follows: C27H44C1FsN; 84% yield;

"calcd. 6.67% Cl; found 6.65% Cl.

Example XV.Octadecyldimethyl-3,5-bis(trifluoromethyl) benzylammonium chloride CH 0H: CHnCl CH2 N-CI 1sHa1 (CHahNOmHar O F 0 Fa 0 Fa C F:

It analyzed as follows: C29H4aC1FeN; 87% yield;

calcd. 6.33% Cl; found 6.26% C1.

Example XVI.--Dodecyldimethyl (2-nitr0-4-trifluoromethyl) phenylammonium chloride CH3 CH3 C1 N-Cl 12 25 2- Nor- (CHshNCu ms CFs Fa Example XVII .Doclecyldimethylchloro-bis(trifluoromethyl) phenylammonium chloride (CHshNCuHzs CH3 CH3 Example XWrI-.-Doaec zaimemgz-4411mm benzylammonium chloride Example XIX.Dodecyltrifluoromethylbenapl CHzCI morpholiniu m chloride Example XX '.D0decyl-bis- (-B-trifluoroethyl-lbenzylammoniu'm chloride CFaOHz 01mm omen, L 0

Emample XXI .-Difluorocetyl-dimethyl-benzylammonium chloride Quaternary ammonium compounds having a fluorine atom on the nitrogen atom may be prepared by converting the corresponding quaternary ammonium chloride to the fluoride by treatment with hydrated silver oxide, to form the hydroxide, followed by neutralization of the hydroxide with aqueous hydrogen fluoride. The following examples are illustrative:

Example XXII .--Dodecyldimeth yl-3- (trifluoromethyl) benzylammonium fluoride Twenty and three-tenth parts (0.05 mole) of dodecyldimethyl 3 (trifluoromethyDbenzylammonium chloride was reacted with hydrated silver oxide to yield dodecy1dimethyl-3- (trifluoromethyDbenzylammonium hydroxide, which was then reacted with aqueou hydrogen fluoride to give the corresponding fluoride. After-purification 6.2 parts of product was recovered. It analyzed as follows: C22H31F4N 3.58 N; found: 3.68% N.

7 Example XXIII .--He:cadeez1Zdimeth1 l-3-(trifluoromethyl) benzylammonium fluoride By comparing the Draves test time of the above dodecyl compounds of this invention with that of a commercial sample of the prior art dodecyldimethylbenzyl ammonium chloride, having a 0111" 5 test time of 374 seconds, it may be seen that the 01,11 corresponding compounds of my invention are at least 16 times more effective, and in the case of dodecyldimethyl-3-(trifluoromethyl) benzyl ammonium fluoride, this compound is. 93 times more Twenty-three and one-tenth parts (0.05 mole) 10 effective as a wetting agent. of the chloride was reactedin the manner of Ex- Also comparison of the Draves test time of the ample XXII. After purification 5.5 parts of prodabove hexadecyl compounds of this invention uct was recovered, and it was found to contain with that of a sample of the prior art hexa 3.13% N. decyl dimethyl benzyl ammonium chloride having The surface active properties of the compounds a test time of 620 seconds, shows my compounds of this invention in Table I were tested by using to be at least about 8 times more effective and the method of Draves (American Dyestufi Reas much as about 25 times more effective than porter, vol. 28, page 425, 1939). The Draves test the corresponding prior art compound. is the time in seconds for a standard 5 gram The bactericidal or germicidal properties of cotton test skein to sink when attached by a the compounds of this invention listed in Table "inch string toa3.0 gram copper hook, when placed II were tested according to the method of the in a cylindrical vessel of 500 ml. capacity with U. S. Food and Drug Administration (Circular the concentration of quaternary of 1.0 gram per 198, December 1931), using E. typhz' and S. aureus. liter. Thus, the shorter the test time, the better exposures were at 20 C.; the results are reportthe wetting power of the compound being tested. ed in phenol coefficients and effective dilutions.

Table II E. typhi S. aureus Min. eflect dil. Min. eflect dil.

Phenol Phenol Coef. Ooef. 5min. 20 min. 5min. 20 min.

11. D0decyldimethyl-4(trl- 05,000 66,000 900 04, 000 65,000 1,000

fiuoromethyl) benzyl ammonium chloride. v11. Dodecyl d1methy13- 70, 000 71,000 875 68,000 72,000 1,200

(trilluoromethyl) benzyl ammonium chloride. XII. Dodecyl dimethyl-3, 50, 000 51,000 000 70,000 71,000 1,100

5-bis (trifluoromethyl) benzyl ammonium chloride. XVIII. Lauryl dimethyl-- 190 480 fluoro benzyl ammonium chloride.

Table I Many of the compounds of my invention, speci- Y fied, are crystalline substances, which may be dis- D av solved in water They are substantially odorless N C d rf f and practically non-toxic to mammals. Certain of the compounds of my invention containing varying amounts of fluorine in the molecule, which possess enhanced germicidal activity and I gggfgggg g figgg 206 very low toxity, are contemplated as being useful 11 Dode fi gi t i gg o e y y 21 in oral therapy as disinfectants, and particularly am 1 e. In Tetradecyl (methyl 4 (gflfluoromethyl) 65 for prevention of dental caries, by virtue of their benzyl ammonium chlori e. fluori t t 1" 11114-111 r111 74 IV y l a mmo r i iiim chlor g uorome y) By means of this invention a whole new class V Octadec ldimethyl 4-(triiluoromethyDben- 304 m a gmonium cmm deof quaternary ammomum compounds 1s made v1 Decyl diinethylll 3 -triiluoromethyl)bcnzyl 42 avallable. Although I have described my invenmm um 0 OH e. i VII Dgdecsflndimethyl 3 (ttifluommethy1)bemy1 23 t.on by illustrating certain specific embodiments Tammoniilmdchlorllldel. 3 mi th 1 46 thereof, various mod1ficat1ons may be made with- VHI igggfg gggf g y) out departing from the spirit and scope there- IX Hexadeeyl dimethyl -(F 84 of, and consequently, I do not intend that itshall benzyl ammomum chloride. x OctadecyldimethylB-(trifluoromethyDb as be limited except as defined 1n the appended zyl ammonium chloride. claims XI Decyldimethy1-3,5-bis(trifluoromethyl)ben- 30 zyl ammonium;1 cllilorittlf. t fi h 1 7 I claim: XII ffiifi g ggf g fifg gf ggf y) 1. A member of the group consisting of a di- XIII et g g f gi iggifg g 13 lower alkyl, higher alkyl, quaternary ammonium me XIV H% d ldi th 1 3 f1:% i g ifl om thyl) 46 salt having a monocyclic aromatic hydrocarbon enzyl ammonium c Ori ring-containing group attached to the penta- -b' '11 h 1 XV t g z fir n fi z l i r n c lil fig. uoromet y) 80 valent nitrogen atom and a N-higher alkyl, mor- Dodlecyl P g tg 4 pholinium quaternary ammonium salt having Z aIIlIIlOIllllIIl L10 8. xx111 Hei r adecyldimethy1-3-trifluoromethyl)ben- 24 a m n h aromatlc hy r n rin nzylammomum fllwfldetaining group attached to the pentavalent nitrogen atom, wherein the aromatic ring contains a 9 fluoromethyl radical, said higher alkyl having from 9 to 13 carbon atoms.

2. A compound according to claim 1 wherein the fluoromethyl radical is a trifluoromethyl radical.

3. A compound according to claim 1 wherein the ring-containing group attached to the pentavalent nitrogen atom is a benzyl group containing at least one trifiuoromethyl radical.

4. A compound according to claim 1 wherein the ring-containing group attached to the pentavalent nitrogen atom is a phenyl group containing at least one trifluoromethyl radical.

5. A compound according to claim 2 wherein a trifluoromethyl radical is attached in the meta position.

6. Dodecyl-dimethyl-3 (trifluoromethyhbem zyl-ammonium chloride.

7. Dodecyldimethyll- (trifiuoromethyl) benzylammonium chloride.

8. Dodecylclimethyl 3,5 bis(trifluoromethyl) benzylammonium chloride.

9. Dodecyl-3- (trifluoromethyl) benzyl-morpholinium chloride.

References Cited in the file of this patent UNITED STATES PATENTS Number 19 Number Name Date 2,108,765 Domagk Feb. 15, 1938 2,209,603 Hentrich May 14, 1940 2,437,833 Niederh et a1 Mar. 16, 1948 FOREIGN PATENTS Number Country Date 49,748 Netherlands 1 Jan. 15, 1941 (Supplement to No. 33,363, May 6, 1936) 194,372 Switzerland Feb. 16, 1938 209,302 Switzerland Dec. 16, 1938 453,633 Great Britain Dec. 8, 1936 576,712 Germany Nov. 29, 1933 866,662 France Dec. 22, 1936 OTHER REFERENCES V/akelin Manufacturing Chemist, vol. 10 (1939) page 18.

Lawrence et al., J. Amer. Pharm. Assoc, vol. 36 (1947) pp. 353-8 Braun et al., Chem. Abstn, vol. 25 (1931), page 925.

Braun et a1., Chem Abstr., vol. 26 (1932), pp. 428 and 429.

McCombie et al., Chem. Abstr., vol. 41 (1947), page 2808. 

1. A MEMBER OF THE GROUP CONSISTING OF A DILOWER ALKYL, HIGHER ALKYL, QUATERNARY AMMONIUM SALT HAVING A MONOCYCLIC AROMATIC HYDROCARBON RING-CONTAINING GROUP ATTACHED TO THE PENTAVALENT NITROGEN ATOM AND A N-HIGH ALKYL, MORPHOLINIUM QUANTERNARY AMMONIUM SALT HAVING A MONOCYCLIC AROMATIC HYDROCARBON RING-CONTAINING GROUP ATTACHED TO THE PENTAVALENT NITOGEN ATOM, WHEREIN THE AROMATIC RING CONTAINS A FLUOROMETHYL RADICAL, SAID HIGHER ALKYL HAVING FROM 9 TO 18 CARBON ATOMS. 